Rapid Stimulation of protein carboxymethylation in leukocytes by a chemotactic peptide

O’Dea, Robert F.; Viveros, O. Humberto; Axelrod, J; Aswanikaumar, S; Schiffmann, Elliott; Corcoran, Barbara

doi:10.1038/272462a0

Cited by 168 publications

(49 citation statements)

References 15 publications

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“…Although fMLP has been reported to have no effect on the level of protein carboxylmethylation in leukocytes and macrophages (27,28), except perhaps transiently (25,26,32,33), some inhibitors of protein carboxylmethylation have been reported to inhibit chemotaxis (25,26,33), whereas others did not (26,27). In at least one study, neither chemotactic agents nor transmethylation inhibitors affected methylation of nucleic acids (25).…”

Section: Discussionmentioning

confidence: 99%

S-adenosylhomocysteine hydrolase is localized at the front of chemotaxing cells, suggesting a role for transmethylation during migration

Shu

Mahadeo

Liu

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Chemotaxis of bacteria requires regulated methylation of chemoreceptors. However, despite considerable effort in the 1980s, transmethylation has never been established as a component of eukaryotic cell chemotaxis. S-adenosylhomocysteine (SAH), the product formed when the methyl group of the universal donor S-adenosylmethionine (SAM) is transferred to an acceptor molecule, is a potent inhibitor of all transmethylation reactions. In eukaryotic cells, this inhibition is relieved by hydrolysis of SAH to adenosine and homocysteine catalyzed by SAH hydrolase (SAHH). We now report that SAHH, which is diffuse in the cytoplasm of nonmotile Dictyostelium amoebae and human neutrophils, concentrates with F-actin in pseudopods at the front of motile, chemotaxing cells, but is not present in filopodia or at the very leading edge. Tubercidin, an inhibitor of SAHH, inhibits both chemotaxis and chemotaxis-dependent cell streaming of Dictyostelium, and chemotaxis of neutrophils at concentrations that have little effect on cell viability. Tubercidin does not inhibit starvationinduced expression of the cAMP receptor, cAR1, or G proteinmediated stimulation of adenylyl cyclase activity and actin polymerization in Dictyostelium. Tubercidin has no effect on either capping of Con A receptors or phagocytosis in Dictyostelium. These results add SAHH to the list of proteins that redistribute in response to chemotactic signals in Dictyostelium and neutrophils and strongly suggest a role for transmethylation in chemotaxis of eukaryotic cells.chemotaxis ͉ Dictyostelium ͉ neutrophils ͉ tubercidin S -adenosylhomocysteine (SAH), the product of the transfer of the methyl group from S-adenosylmethionine (SAM) to DNA, RNA, phospholipids and many small molecules ( Fig. 1), is a strong inhibitor of transmethylation (1). The inhibition is relieved in prokaryotes by hydrolysis of SAH to adenine and ribosylhomocysteine (2), and in eukaryotes by hydrolysis of SAH to adenosine and homocysteine, catalyzed by SAH hydrolase (SAHH) (3). Because hydrolysis of SAH is reversible, and more favored in the synthetic direction, efficient transmethylation from SAM in eukaryotes also requires removal of adenosine and homocysteine (Fig. 1).Stimulated by the discovery in the mid-1970s that bacterial chemotaxis is initiated by SAM-dependent transient carboxyl-O-methylation of glutamic acid residues in chemotactic ligand receptor proteins (4, 5), the possibility that transmethylation reactions have a role in the chemotactic response of Dictyostelium and leukocytes was investigated in the early 1980s. Investigators asked whether chemotactic factors increase methylation of proteins, phospholipids, and/or nucleic acids, and whether inhibition of methylation by inhibiting SAHH or adenosine deaminase inhibits chemotaxis. The results of these studies were inconclusive and often contradictory (see Discussion).In the contemporary view of chemotaxis of Dictyostelium and leukocytes, chemoattractants mediate their effects by binding to transmembrane receptors coupled to heterotrimer...

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Section: Discussionmentioning

confidence: 99%

S-adenosylhomocysteine hydrolase is localized at the front of chemotaxing cells, suggesting a role for transmethylation during migration

Shu

Mahadeo

Liu

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…Furthermore, Bynum and Volkin (43) have found that adenosine selectively interferes with the accumulation of 18S rRNA in human myeloma cells, and it is very likely that this effect is secondary to AdoHcy accumulation with the resultant inhibition of pre-rRNA methylation. Other possible targets of AdoHcy toxicity include: protein carboxy-O-methylation (44,45), a reaction believed to be involved in certain specialized processes such as chemotaxis (46,47), secretion (48), and neural function (49); histone methylation (50,51); and the metabolism of small molecules such as phospholipids (52,53) and carnitine (54).…”

Section: Discussionmentioning

confidence: 99%

S -Adenosylhomocysteine toxicity in normal and adenosine kinase-deficient lymphoblasts of human origin

Kredich

Hershfield

1979

Proc. Natl. Acad. Sci. U.S.A.

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The human lymphoblast line WI-L2 is subject to growth inhibition by a combination of the adenosine deaminase (ADA; adenosine aminohydrolase, EC 3.5.4.4.) inhibitor erythro-9-2-hydroxy-3-nonyl)adenine (EHNA) and adenosine.Although adenosine-induced pyrimidine starvation appears to contribute to this effect, uridine only partially reverses adenosine toxicity in WI-L2 and not at all in strain 107, an adenosine kinase(ATP:adenosine 5'-phosphotransferase, EC 2.7.1.20) deficient derivative of WI-L2. Treatment of both cell lines with EHNA and adenosine leads to striking elevations in intracellular S-adenosyl-L-homocysteine (AdoHcy), a potent inhibitor of Sadenosyl-L-methionine (AdoMet)-dependent methylation reactions. The methylation in vivo of both DNA and RNA is inhibited by concentrations of EHNA and adenosine that elevate intracellular AdoHcy. Addition of 100 jiM L-homocysteine thiolactone to cells treated with EHNA and adenosine enhances adenosine toxicity and further elevates Adolcy to levels approximately 60-fold higher than those obtained in the absence of this amino acid, presumably by combining with adenosine to form AdoHcy in a reaction catalyzed by S-adenosylhomocysteine hydrolase (EC 3.3.1.1). In the adenosine kinase-deficient strain 107, a combination of ADA inhibition and L-homocysteine thiolactone markedly increases intracellular AdoHcy and inhibits growth even in the absence of exogenous adenosine. These results demonstrate a form of toxicity from endogenously produced adenosine and support the view that AdoHcy, by inhibiting methylation, is a mediator of uridine-resistant adenosine toxicity in these human lymphoblast lines. Furthermore, they suggest that AdoHcy may play a role in the pathogenesis of the severe combined immunodeficiency disease found in most children with heritable ADA deficiency.

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“…In the majority of cases, the role of methylation is unclear, although the turnover of protein methyl groups is well known to be a regulatory mechanism in bacterial chemotaxis [45, 461 and a similar system may operate in mammalian leukocytes [47]. Myosin is a good example of a methylated protein containing, in addition to Me,Ala, 1 mol 3-methylhistidine [48], 1 mol E-Nmonomethyllysine and 2 mol E-N-trimethyllysine [30] per mol heavy chain, all located in the S 1 region.…”

Section: Characterization Of the N-terminal Peptides From Bovine Cardmentioning

confidence: 99%

The widespread distribution of α‐N‐trimethylalanine as the N‐terminal amino acid of light chains from vertebrate striated muscle myosins

Henry

Trayer

Brewer

et al. 1985

European Journal of Biochemistry

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Identical tripeptides of the sequence X‐Pro‐Lys, where X is an unknown blocking group, were isolated from trypsin digests of bovine cardiac alkali light chain and the LC2 light chain of rabbit fast muscle. Chemical, electrophoretic and 1H‐NMR evidence characterized X as an unusual amino acid, α‐N‐trimethylalanine (Me3Ala), which was earlier reported as the N‐terminal amino acid of the A1 alkali light chain of rabbit fast muscle [Henry et al. (1982) FEBS Lett. 144, 11–15]. The narrow line width and chemical shift position (δ= 3.23 ppm) of the –N+ ‐(CH3) protons of Me3Ala made 1H‐NMR spectroscopy a convenient method to search for this residue in other light chains. A survey of many different light chains showed that this signal was present in all vertebrate striated muscle light chains of the A1‐type (LC1, ‘essential’ light chains) and LC2‐type (‘DTNB’‐light chains, ‘phosphorylatable’ light chains) but was absent from all invertebrate muscle and vertebrate smooth muscle light chains tested. It was also absent from the vertebrate fast‐muscle‐specific A2‐type (LC3) light chains. The spectral characteristics of these signals were consistent with their having arisen from the protons of an – N+ ‐(CH3)3 grouping. Since no ɛ‐trimethyllysine could be detected in acid hydrolysates of these proteins, it appears that Me3Ala is a general feature as the N‐terminal amino acid in these light chains. 1H‐NMR studies on bovine cardiac myosin subfragment 1 (S1) showed that the Me3Ala methyl proton signal was clearly visible and that the spectrum more closely resembled that of a rabbit S1 isoenzyme, S1(A1), than S1(A2), suggesting that the 40‐residue N‐terminal segment of the alkali light chain in cardiac S1 also possesses a high segmental mobility. Addition of actin caused the same gross changes to the cardiac S1 spectrum as noted earlier for rabbit S1(A1) [Prince et al. (1981) Eur. J. Biochem. 121, 213–219]. In particular, a marked reduction in the segmental mobility of the N‐terminal region of the alkali light chain was noted, consistent with a direct interaction of this area with actin.

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Rapid Stimulation of protein carboxymethylation in leukocytes by a chemotactic peptide

Cited by 168 publications

References 15 publications

S-adenosylhomocysteine hydrolase is localized at the front of chemotaxing cells, suggesting a role for transmethylation during migration

S-adenosylhomocysteine hydrolase is localized at the front of chemotaxing cells, suggesting a role for transmethylation during migration

S -Adenosylhomocysteine toxicity in normal and adenosine kinase-deficient lymphoblasts of human origin

The widespread distribution of α‐N‐trimethylalanine as the N‐terminal amino acid of light chains from vertebrate striated muscle myosins

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